Vaccine. 2019 Mar 5. pii: S0264-410X(19)30209-9. doi: 10.1016/j.vaccine.2019.02.015. [Epub ahead of print]
Inflammatory parameters associated with systemic reactogenicity following vaccination with adjuvanted hepatitis B vaccines in humans.
Burny W1, Marchant A2, Hervé C3, Callegaro A3, Caubet M3, Fissette L3, Gheyle L4, Legrand C5, Ndour C5, Tavares Da Silva F3, van der Most R3, Willems F2, Didierlaurent AM3, Yarzabal J3; ECR-008 study group.
Author information
1
GSK, Rixensart/Wavre, Belgium. Electronic address: [email protected].
2
Institute for Medical Immunology, Université libre de Bruxelles, Charleroi, Belgium.
3
GSK, Rixensart/Wavre, Belgium.
4
SGS Life Science Services, Antwerp, Belgium.
5
Institute of Statistics, Biostatistics and Actuarial Sciences (ISBA), Université Catholique de Louvain, Louvain-la-Neuve, Belgium.
Abstract
BACKGROUND:
Adjuvants like AS01B increase the immunogenicity of vaccines and generally cause increased transient reactogenicity compared with Alum. A phase II randomized trial was conducted to characterize the response to AS01B and Alum adjuvanted vaccines. A post-hoc analysis was performed to examine the associations between reactogenicity and innate immune parameters.
METHODS:
The trial involved 60 hepatitis B-naïve adults aged 18-45 years randomized 1:1 to receive either two doses of HBsAg-AS01B on Day (D)0 and D30, or three doses of HBsAg-Alum on D0, D30, D180. Prior to vaccination, all subjects received placebo injection in order to differentiate the impact of injection process and the vaccination. Main outcomes included reactogenicity symptoms, vital signs, blood cytokines, biochemical and hematological parameters after vaccination. Associations were explored using linear regression.
FINDINGS:
The vaccine with AS01B induced higher HBsAg-specific antibody levels than Alum. Local and systemic symptoms were more frequent in individuals who received HBsAg AS01B/Alum vaccine or placebo, but were mild and short-lived. Blood levels of C-reactive protein (CRP), bilirubin, leukocyte, monocyte and neutrophil counts increased rapidly and transiently after AS01B but not after Alum or placebo. Lymphocyte counts decreased in the AS01B group and lactate dehydrogenase levels decreased after Alum. Modelling revealed associations between systemic symptoms and increased levels of CRP and IL-6 after the first HBsAg-AS01B or HBsAg-Alum immunization. Following the second vaccine dose, CRP, IL-6, IP-10, IFN-γ, MIP-1β and MCP-2 were identified as key parameters associated with systemic symptoms. These observations were confirmed using an independent data set extracted from a previous study of the immune response to HBsAg-adjuvanted vaccines (NCT00805389).
CONCLUSIONS:
IL-6 and IFN-γ signals were associated with systemic reactogenicity following administration of AS01B-adjuvanted vaccine. These signals were similar to those previously associated with antibody and T-cell responses induced by HBsAg-adjuvanted vaccines, suggesting that similar innate immune signals may underlie adjuvant reactogenicity and immunogenicity.
TRIAL REGISTRATION:
含有AS01B的疫苗诱导的HBsAg特异性抗体水平高于明矾。接受HBsAg AS01B /明矾疫苗或安慰剂的患者出现局部和全身症状较为频繁，但症状轻微且寿命短。在第一次HBsAg-AS01B或HBsAg-明矾免疫后，C-反应蛋白（CRP）bili bili bili bili bili bili bili bili bili IL-6的血液水平。在第二次疫苗剂量后，CRP，IL-6，IP-10，IFN-γ，MIP-1β和MCP-2被鉴定为与系统性相关的关键参数。这些观察结果使用从先前研究中提取的独立数据集确认。对HBsAg佐剂疫苗的免疫应答（NCT00805389）。
结论：